Rickettsia are obligate intracellular bacteria that can cause anemia, leukopenia, thrombocytopenia, or vasculitis depending on the host cell infected. In animals that survive acute infection, many rickettsia establish lifelong persistent infection in the face of high antibody titers and T lymphocyte responsiveness that mediate resistance to challenge with the initial infecting strain. How rickettsia persist despite an effective immune response is unknown. Importantly, persistently infected animals provide a reservoir for arthropod-borne transmission of rickettsia to additional susceptible hosts. A. marginale is an intraerythrocytic rickettsia of cattle in which infection persists for the life of the animal. During persistent A. marginale infection, cyclic rickettsemia in the face of an effective immune response suggests the emergence of antigenic variants. Genomic and antigenic diversity is evident in the multigene family encoding the A. marginale major surface protein 2 (MSP-2), a putative adhesin for erythrocyte binding that has been shown to be an important target for immune responses during control of acute rickettsemia. The proposed project tests the hypothesis that MSP-2 antigenic variants emerge during rickettsemic cycles in persistent A. marginale infection. Identifying molecules that vary during persistent infection can then direct research towards molecular mechanisms of antigenic variation. Determining mechanisms of persistence in A. marginale infection may direct new approaches for controlling persistence and transmission of A. marginale and other rickettsia.